An important and significant goal in healthcare is to discover and make available safer and more effective drugs for the treatment of cancer. Most chemotherapeutic agents act by disrupting DNA metabolism, DNA synthesis, DNA transcription, or microtubule spindle function, or by perturbing chromosomal structural integrity by introducing DNA lesions.
One important chemotherapeutic in the treatment of cancer is taxol, also known as paclitaxel, which first was isolated from the Pacific yew tree in 1971 (M. C. Wani et al., J. Am. Chem. Soc., 93, 2325–2327 (1971)). Taxol enhances polymerization of tubulin and forms stable microtubule polymers. More recent studies indicate that paclitaxel binding to Bcl-2 may involve a second pathway to apoptosis.
The clinical effectiveness of taxol (1) is well recognized. Since its approval in 1992, taxol has prolonged the lives of more than 800,000 patients with ovarian, breast, and lung carcinomas. The sales of taxol in 2000 alone exceeded $1.6 billion. Recently, taxol has been approved for treatment of myeloid leukemia and has shown promise in the treatment of a number of other carcinomas, including the skin, head, and neck.
The introduction of taxol, a plant-derived anticancer agent, is an example of the importance of natural products in the treatment of complex human diseases. However, despite its clinical successes, taxol possesses a number of major limitations including: (i) debilitating side effects; (ii) poor aqueous solubility leading to complexities in its formulation; (iii) ineffectiveness against colon cancer and many other carcinomas, and critically, (iv) significant loss of therapeutic value due to the emergence of P-glycoprotein mediated multidrug-resistance (MDR), as well as drug-induced resistance-conferring tubulin mutations.
The clinical usefulness and commercial success of taxol has stimulated intense research to find other antimitotic agents that overcome many of the disadvantages associated with taxol and, therefore, provide new cancer treatments having improved therapeutic profiles. As a result, several pharmaceutical companies currently are performing clinical trials using other microtubule stabilizing agents, such as the epothilones and discodermolides.
A number of these novel natural products deviate from the taxoid platform, and still exhibit microtubule-stabilizing properties. In particular, the epothilones (A and B) and their analogs have generated interest because of a less complex structure than taxol, a minimal structural analogy to taxol, and significant biological properties (K. C. Nicolaou et al., Agnew. Chem., 37, 2014–2045 (1998)).

Epothilones A and B were isolated as a cytotoxic antifungal agent from a strain of myxobacteria found in soil. Subsequently, it was discovered that the epothilones stabilize microtubule assemblies and their mode of action is similar to that of taxol. Competitive binding studies indicated that the epothilones occupy a similar binding site on microtubules as [3H]taxol. Furthermore, the epothilones maintain cytotoxicity against P-glycoprotein expressing MDR cells. In addition, the epothilones are active against a number of taxol-resistant cell lines.
An epothilone derivative, BMS-247550 (5), has shown improved properties compared to epothilone B and is undergoing clinical trials. Another epothilone analog, desoxyepothilone B (6), is as potent, and less toxic, than epothilone B (4). Recent in vivo studies using compound (6) showed that it is less toxic and more effective than taxol in an MX-1 human mammary carcinoma xenograft model. Discodermolide (7), another nontaxane natural product isolated from a Caribbean sponge, also has been shown to inhibit mitosis and promote tubulin assembly more potently than taxol. Compound (7) also is an effective inhibitor of cell growth in taxol-resistant cell lines. Eleutherobin (8) and a related aglycon, sarcodictyin A, also have been shown to bind to the taxol site of microtubules. However, these compounds exhibit cross resistance to taxol-resistant cell lines.

Laulimalide (2), also known as figianolide B, is an 18-membered macrolide isolated in miniscule quantities from the marine sponge Cacospongia mycofijiensis (E. Quinoa et al., J. Org. Chem., 53, 3642–4644 (1988)). Corey et al. (J. Org. Chem., 53, 3644–3646 (1988)) also isolated laulimalide from the Indonesian sponge Hyattella sp. Laulimalide possesses significant antitumor properties, and has generated significant attention in recent years because laulimalide shares the same mechanism of action as taxol.
Laulimalide demonstrates potent microtubule-stabilizing properties and also displays significant antitumor properties against numerous cell lines. For example, laulimalide displays cytotoxicity against the KB cell line with an IC50 value of 15 ng/mL, and its cytotoxicity against P388, A549, HT29, and MEL28 cell lines ranged from 10–50 ng/mL (IC50 values). In two drug-sensitive cell lines, MDA-MB-435 and SK-OV-3, laulimalide is a potent inhibitor of cell proliferation with IC50 values of 5–12 nM compared to 1–2 μM for taxol. Furthermore, laulimalide maintained a high level of potency against the multidrug resistant cell line SKVLB-1 (IC50=1.2 μM). In contrast, isolaulimalide (a) is significantly less potent against the KB cell line (IC50>200 nM) and the SKVLB-1 line (IC50=2.6 μM). More importantly, laulimalide is 100-fold more potent than taxol against P-glycoprotein-mediated MDR cell lines.
The unique structural features, potent microtubule-stabilizing properties, and low natural abundance of laulimalide stimulated interest in its synthesis, structure-activity studies, tubulin binding properties, and molecular and cell biology. The first total synthesis of (−)-laulimalide (2) was reported in A. K. Ghosh et al., J. Org. Chem., 66, 8973–8982 (2001) and A. K. Ghosh et al. J. Am. Chem. Soc., 122, 11027–11029 (2000), incorporated herein by reference.
Laulimalide also has a considerable structural resemblance to the epothilones, which have generated major interest due to their activity against drug-resistant cell lines. Laulimalide shares a common pharmacophore with respect to the epothilones, yet possesses unique structural features. Based upon a structural resemblance to the epothilones, and because laulimalide possesses the same mechanism of action, it initially was hypothesized that laulimalide shared the same binding site as the epothilones. However, it now is evident that the laulimalide binding site is distinct from the binding site of taxol and the epothilones. Research already has shown that epothilones are competitive inhibitors of taxol.
The present invention is directed to compounds that provide the benefits of taxol, while overcoming various disadvantages associated with taxol, including multidrug resistance. Such compounds are analogs of laulimalide and the epothilones, and can be used in methods of treating various carcinomas, including, but not limited to, breast, refractory ovarian, small-cell lung, myeloid leukemia, metastatic carcinomas, and carcinomas of the skin, head, and neck. More particularly, the present invention is directed to more potent and less structurally complex analogs of laulimalide and the epothilones, in optically active form, that demonstrate biological activities and are useful in the treatment of cancers.